Studies raise questions over how epigenetic information is inherited

October 29, 2018, University of Cambridge
Credit: CC0 Public Domain

Evidence has been building in recent years that our diet, our habits or traumatic experiences can have consequences for the health of our children—and even our grandchildren. The explanation that has gained most currency for how this occurs is so-called 'epigenetic inheritance' - patterns of chemical 'marks' on or around our DNA that are hypothesised to be passed down the generations. But new research from the University of Cambridge suggests that this mechanism of non-genetic inheritance is likely to be very rare.

A second study, also from Cambridge, suggests, however, that one way that environmental effects are passed on may in fact be through molecules produced from the DNA known as RNA that are found in a father's sperm.

The mechanism by which we inherit innate characteristics from our parents is well understood: we inherit half of our genes from our mother and half from our father. However, the mechanism whereby a 'memory' of the parent's environment and behaviour might be passed down through the generations is not understood.

Epigenetic inheritance has proved a compelling and popular explanation. The human genome is made up of DNA—our genetic blueprint. But our genome is complemented by a number of 'epigenomes' that vary by cell type and developmental time point. Epigenetic marks are attached to our DNA and dictate in part whether a gene is on or off, influencing the function of the gene. The best understood epigenetic modification is DNA methylation, which places a group on one of the bases of DNA (the A, C, G or T that make up our ).

One model in which DNA methylation is associated with is a mouse mutant called Agouti Viable Yellow. The coat of this mouse can be completely yellow, completely brown, or a pattern of these two colours—yet, remarkably, despite their different coat colours, the mice are genetically identical.

The explanation of how this occurs lies with epigenetics. Next to one of the key genes for coat colour lies a section of genetic code known as a 'transposable element' - a small mobile DNA 'cassette' that is actually repeated many times in the mouse genome but here acts to regulate the coat colour gene.

As many of these transposable elements come from external sources—for example, from a virus's genome—they could be dangerous to the host's DNA. But organisms have evolved a way of controlling their movement through methylation, which is most often a silencing epigenetic mark.

In the case of the gene for coat colour, if methylation switches off the transposable element completely, the mouse will be brown; if acquisition of methylation fails completely, the mouse will be yellow. But this does not affect the genetic code itself, just the epigenetic landscape of that DNA segment.

And yet, a yellow-coated female is more likely to have yellow-coated offspring and a brown-coated female is more likely to have brown-coated offspring. In other words, the epigenetically regulated behaviour of the is somehow being inherited from parent to offspring.

A team led by Professor Anne Ferguson-Smith at Cambridge's Department of Genetics set out to examine this phenomenon in more detail, asking whether similar variably-methylated transposable elements existed elsewhere that could influence a mouse's traits, and whether the 'memory' of these could be passed from one generation to the next. Their results are published in the journal Cell.

The researchers found that while these transposable elements were common throughout the genome—transposable elements comprise around 40% of a mouse's total genome—the vast majority were completely silenced by methylation and hence had no influence on genes.

Only around one in a hundred of these sequences were variably-methylated. Some of these are able to regulate nearby genes, whereas others may have the ability to regulate genes located further away in the genome in a long-range capacity.

When the team looked at the extent to which the methylation patterns on these regions could be passed down to subsequent generations, only one of the six regions they studied in detail showed evidence of epigenetic inheritance—and even then, the effect size was small. Furthermore, only methylation patterns from the mother, not the father, were passed on.

"One might have assumed that all the variably-methylated elements we identified would show memory of parental epigenetic state, as is observed for in Agouti Viable Yellow mice," says Tessa Bertozzi, a Ph.D. candidate and one of the study's first authors. "There's been a lot of excitement and hype surrounding the extent to which our epigenetic information is passed on to subsequent generations, but our work suggests that it's not as pervasive as was previously thought."

"In fact, what we showed was that methylation marks at these transposable elements are reprogrammed from one generation to the next," adds Professor Ferguson-Smith. "There's a mechanism that removes methylation from the vast majority of the genome and puts it back on again, once in the process of generating eggs and sperms and again before the fertilised egg implants into the uterus. How the methylation patterns at the regions we have identified get reconstructed after this genome-wide erasure is still somewhat of a mystery.

"We know there are some genes—imprinted genes for example- that do not get reprogrammed in this way in the early embryo. But these are exceptions, not the rule."

Professor Ferguson-Smith says that there is evidence that some environmentally-induced information can somehow be passed down generations. For example, her studies in mice show that the offspring of a mother who is undernourished during pregnancy are at increased risk of type 2 diabetes and obesity—and their offspring will in turn go on to be obese and diabetic. Again, she showed that DNA methylation was not the culprit—so how does this occur?

The answer may come from research at the Wellcome/Cancer Research UK Gurdon Institute, also at the University of Cambridge, in collaboration with the lab of Professor Isabelle Mansuy from the University of Zürich and Swiss Federal Institute of Technology. In a study carried out in mice and published in the journal Molecular Psychiatry, they report how the 'memory' of early life trauma can be passed down to the next generation via RNA molecules carried by sperm.

Dr. Katharina Gapp from the Gurdon Institute and the Mansuy lab have previously shown that trauma in postnatal life increases the risk of behavioural and metabolic disorders not only in the directly exposed individuals but also in their subsequent offspring.

Now, the team has shown that the trauma can cause alterations in 'long RNA' (RNA molecules containing more than 200 nucleotides) in the father's sperm and that these contribute to the inter-generational effect. This complements earlier research that found alterations in 'short RNA' molecules (with fewer than 200 nucleotides) in the sperm. RNA is a molecule that serves a number of functions, including, for some of the long versions called messenger RNA, 'translating' DNA code into functional proteins and regulating functions within cells.

Using a set of behavioural tests, the team showed that specific effects on the resulting offspring mediated by long RNA included risk-taking, increased insulin sensitivity and overeating, whereas small RNA conveyed the depressive-like behaviour of despair.

Dr. Gapp said: "While other research groups have recently shown that small RNAs contribute to inheritance of the effects of chronic stress or changes in nutrition, our study indicates that long RNA can also contribute to transmitting some of the effects of early life trauma. We have added another piece to the puzzle for potential interventions in transfer of information down the generations."

Explore further: Inherited 'memory' of environmental impact on health may be limited

More information: K. Gapp et al, Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma, Molecular Psychiatry (2018). DOI: 10.1038/s41380-018-0271-6

Related Stories

Inherited 'memory' of environmental impact on health may be limited

July 10, 2014
When a pregnant mother is undernourished, her child is at a greater than average risk of developing obesity and type 2 diabetes, in part due to so-called 'epigenetic' effects. A new study in mice demonstrates that this 'memory' ...

Study documents paternal transmission of epigenetic memory via sperm

October 17, 2018
Studies of human populations and animal models suggest that a father's experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across ...

Epigenetic reprogramming: Research discovers how epigenetic information could be inherited

January 24, 2013
New research reveals a potential way for how parents' experiences could be passed to their offspring's genes. The research was published today, 25 January, in the journal Science.

DNA marks in adults tracked back to changes in earliest days of life

July 11, 2018
Scientists have gained a glimpse of how marks on our genes that could be linked to adverse health outcomes in later life behave differently in the first few days after conception, according to new research published in Science ...

Reprogramming of DNA observed in human germ cells for first time

June 4, 2015
A team of researchers led by the University of Cambridge has described for the first time in humans how the epigenome - the suite of molecules attached to our DNA that switch our genes on and off - is comprehensively erased ...

Study shows how epigenetic memory is passed across generations

September 18, 2014
A growing body of evidence suggests that environmental stresses can cause changes in gene expression that are transmitted from parents to their offspring, making "epigenetics" a hot topic. Epigenetic modifications do not ...

Recommended for you

Scientists identify method to study resilience to pain

December 14, 2018
Scientists at the Yale School of Medicine and Veterans Affairs Connecticut Healthcare System have successfully demonstrated that it is possible to pinpoint genes that contribute to inter-individual differences in pain.

CRISPR joins battle of the bulge, fights obesity without edits to genome

December 13, 2018
A weighty new study shows that CRISPR therapies can cut fat without cutting DNA. In a paper published Dec. 13, 2018, in the journal Science, UC San Francisco researchers describe how a modified version of CRISPR was used ...

Noncoding mutations contribute to autism risk

December 13, 2018
A whole-genome sequencing study of nearly 2,000 families has implicated mutations in 'promoter regions' of the genome—regions that precede the start of a gene—in autism. The study, which appears in the December 14 issue ...

New method for studying ALS more effectively

December 13, 2018
The neurodegenerative disease ALS causes motor neuron death and paralysis. However, long before the cells die, they lose contact with muscles as their axons atrophy. Researchers at Karolinska Institutet in Sweden have now ...

Paternal grandfather's high access to food may indicate higher mortality risk in grandsons

December 12, 2018
A paternal grandfather's access to food during his childhood is associated with mortality risk, especially cancer mortality, in his grandson, shows a large three-generational study from Stockholm University. The reason might ...

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.


Adjust slider to filter visible comments by rank

Display comments: newest first

1 / 5 (1) Oct 30, 2018
But organisms have evolved a way of controlling their movement through methylation, which is most often a silencing epigenetic mark.

All the rest of the research is very impressive indeed and one can only hope they'll be as creative at finding out even more about epi-genetic factors and their propagation.
However, in this quote, they are appealing to the god of evolution instead which is really a very bad move for researchers. It would be so much better to ditch the evolutionary nonsense and search out the real facts behind the controls. It should be all logical, with no reference to the mythical naturalistic god. That kind of behavior impedes science enormously.
not rated yet Oct 31, 2018
"Using a set of behavioural tests, the team showed that specific effects on the resulting offspring mediated by long RNA included risk-taking, increased insulin sensitivity and overeating, whereas small RNA conveyed the depressive-like behaviour of despair."

I wasn't aware that "Mouse Psychology" was a new field of expertise in the already mushy "soft science" of Psychology in general. I guess there has to be openings now -for Mouse Psycho-therapist.
not rated yet Nov 01, 2018
The most stable forms of epigenetic inheritance are histone markers. Those researchers didn't take into account them or some other significant epigenetic information layers. More about them in here: https://humgenomi...5-0041-3

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.